MX2012015198A - PREPARATION OF 13-CYCLOHEXYL-3-METHOXY-6-[METHYL-(2-{2-[METHYL-(S ULPHAMOYL)-AMINO]-ETHOXY}-ETHYL)-CARBAMOYL]-7<i>H</i>-INDOLO-[2, 1-a]-[2]-BENZAZEPINE-10-CARBOXYLIC ACID. - Google Patents

PREPARATION OF 13-CYCLOHEXYL-3-METHOXY-6-[METHYL-(2-{2-[METHYL-(S ULPHAMOYL)-AMINO]-ETHOXY}-ETHYL)-CARBAMOYL]-7<i>H</i>-INDOLO-[2, 1-a]-[2]-BENZAZEPINE-10-CARBOXYLIC ACID.

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Publication number
MX2012015198A
MX2012015198A MX2012015198A MX2012015198A MX2012015198A MX 2012015198 A MX2012015198 A MX 2012015198A MX 2012015198 A MX2012015198 A MX 2012015198A MX 2012015198 A MX2012015198 A MX 2012015198A MX 2012015198 A MX2012015198 A MX 2012015198A
Authority
MX
Mexico
Prior art keywords
methyl
acid
ethyl
ethoxy
compound
Prior art date
Application number
MX2012015198A
Other languages
Spanish (es)
Inventor
Jean-Pierre Andre Marc Bongartz
Patrick Hubert J Nieste
Tom Cornelis Hortense Govaerts
Original Assignee
Janssen R & D Ireland
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen R & D Ireland filed Critical Janssen R & D Ireland
Publication of MX2012015198A publication Critical patent/MX2012015198A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C307/04—Diamides of sulfuric acids
    • C07C307/06—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to an improved method for the preparation of 3-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-ami no]-ethoxy}- ethyl)-carbamoyl]-7<i>H</i>-indolo-[2,1-a]-[2]-benzazepine-10-c arboxylic acid. The present invention also relates to a new compound, namely tert-butyl (methyl-{2-[2-(methylamino)-ethoxy]-ethyl}-sulphamoyl)-carbamat e, used in this improved method.

Description

PREPARATION OF 13-CYCLOHEXYL-3-METOXY-6-rMETIL- (2- (2-rMETIL- (SULFAMOIL) -AMIN01-ETOXI) -ATILE) -CARBAMOYL1-7H-INDOLO-r2.1-a1-r21-BENZAZEPIN -10-CARBOXYLIC DESCRIPTIVE MEMORY The present invention relates to an improved method for the preparation of 13-cyclohexyl-3-methoxy-6- [methyl- (2- {2- [methyl- (sulfamoyl) -amino] -ethoxy} acid. ethyl) -carbamoyl] -7H-indolo- [2-a] - [2] -benzazepin-10-carl-oxyl. present invention also relates to a new compound, mainly tert-butyl (methyl-. {2- [2- (methylamino) -ethoxy] -ethyl} - sulfamoyl) - carbamate, used in this proper method. 13-cyclohexyl-3-methoxy-6 [methyl. { 2- [Methyl- (sulfamoyl) -amino] -ethoxy} ethyl) -carbamoyl] -7H-indolo- [2, 1-a] - [2] -benzazepine-10-carboxylic acid Compound 'A' fer-butyl (methyl-. {2- [2- (methylamino) ethoxy] -ethyl.} - sulfamoyl) -carbamate Compound 'B' WO 2010/003658 describes some macrocyclic characters that can be used as inhibitors of the hepatitis C virus. The synthesis of 13-dclohexyl-3-methoxy-6- [methyl- (2-. {2- [methyl- ( sulfamoyl) -amino] -ethoxy.} -ethyl) - The coupling agent in Step a) is for example I carbodiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 0- (7-azabenztriazoM-yl) -1, 1, 3,3-tetramethyluronium hexafluorophosphate (HATU), bromotri- (pyrrolidino) -phosphonium hexafluorophosphate (PyBrOP), a combination |; of 1-hydroxybenztriazole hydrate (HOBt.h ^ O) and hydrochloride | 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (EDCI).
A suitable solvent in Step a) is, for example, dichloromethane, 2-methyltetrahydrofuran, acetonitrile, acetone, 2-bujanone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate or toluene.
The hydrolysis in Step b) can be carried out using trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, hydrogen bromide, para-toluenesulfonic acid, sulfuric acid or phosphoric acid .; Steps a) and b) can be carried out as a two-step synthesis, where Compound (II) is isolated in Step a) before carrying out Step b), or Steps a) and b) ) are made as a synthesis of a container All the performance obtained in Steps a) and b) is] between 86 and 91%, depending on which of the procedures described in Examples 3, 4 and 5 (Experiment B) is used to carry out the new method.
The present invention also relates to a new compound (Compound 'B') with the following formula, and possible acid addition salts thereof: tert -Butyl- (methyl-. {2- [2- (methylamino) -ethoxy] -ethyl} -sulfamoyl) -carbamate (Compound 'B') The acid addition salts of Compound 'B' include the salts that Compound '?' it can form with organic or inorganic acids, such as mineral acids, sulfonic acids, carboxylic acids and acids containing phosphorus. Examples of the mineral acids which form the salt are hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, doric acid, perchloric acid and phosphoric acid. The sulfonic acids which form the salt are toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid. The carboxylic acids which form the salt are formic acid, acetic acid, propionic acid, butanoic acid and the like. The dicarboxylic acids which form the salt are oxalic acid, malonic acid, succinic acid, glutaric acid and the like. The hydroxy acids that form the salt are glycolic acid, acid lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and the like. Other carboxylic acids which form the salt are trifluoroacetic acid, benzoic acid, chloroacetic acid, italic acid, maleic acid and malonic acid.
The acids that contain phosphorus are several phosphono-acids, acids | phosphonic and phosphinic acids.
This new Compound 'B' can be synthesized as follows: Step 1 : Experimental The following abbreviations are used in a present: A / A: active performance CDI: carbonyldiimidazole CSI: chlorosulfonyl isocyanate I DBU: 1, 8-diaza-bicyclo- [5,4,0] -undecene-7 DIPE: diisopropyl ether DMAP: 4-dimethylaminopyridine DME: 1,2-dimethoxyethane DMSO-d6: deuterated dimethylsulfoxide EDCI: 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride F / F: physical performance HOBt: hydrated 1-hydroxybenzotriazole PrOAc: isopropyl acetate LC: liquid chromatography MeCN: acetonitrile MEK: methyl ethyl ketone (2-butanone) MeTHF: 2-methyltetrahydrofuran MeS03H: methanesulfonic acid MIK: methyl isopropyl ketone MTBE: methyl ether-butyl ether NMR: nuclear magnetic resonance tBuOH: tert-butanol tBOC: tert-butoxycarbonyl THF: tetrahydrofuran environment and sample was taken again for analysis. The entire reaction mixture weighed 15,022 g.
Analysis by LC After 5 hours: 90.1% of Compound 'A' After 22 hours: 75.4% of Compound 'A' Experiment B: 19. 6 g of the Intermediary (2) (10.27% by weight, 15.7 rhmoles, 1 Ec) was dissolved in MeTHF (8 l / mole) in a reaction vessel under a nitrogen atmosphere. The solution contained 2.21% by weight of water. 2.81 g of water was added to bring the water content up to 4% by weight After the addition of 10.31 ml of MeSO3H (157 mmol, 10 Ec), the reaction mixture was heated to 50 ° C. After a reaction time of 5 hours, the reaction mixture was cooled to room temperature and a sample thereof was analyzed. The entire reaction mixture weighed 119.6 g.
Analysis by LC 92. 7% of Compound 'A'

Claims (1)

  1. NOVELTY OF THE INVENTION CLAIMS 1. - A method for the preparation of 13-cyclohexyl-3-methoxy-6- [methyl- (2- {2- (methyl- (sulfamoyl) -amino] -ethoxy} -ethyl) -carbamoyl] - acid 7 / - / - indolo- [2,1-a] - [2] -benzazepin-10-carboxylic acid ('Compound A'), characterized in that it comprises the following steps: a) acid is reacted: butoxycarbonyl) -13-cyclohexyl-3-methoxy-7H-indole- [2, 1-a] - [2] -benzaze-h-6-carboxylic acid (Compound I) with fer-butyl (methyl-) {2- [2- (methylamino) ethoxy] -ethyl.}. -sulfamoyl) -carbamate (Compound '?') In the presence of a coupling agent in a suitable solvent, and b) Compound (II) thus obtained is hydrolyzed with an acid, so that Compound? is obtained. 6. - The method according to claim 5, further characterized in that the solvent used in Step a) is 2-methyltetrahydrofuran. 7. - The method according to claim 6, further characterized in that the organic acid used in Step b) is methanesulfonic acid, the reaction temperature is 50 ° C, and the duration of the reaction is not greater than 5 hours. 8. - tert-Butyl (methyl-. {2- [2- (methylamino) -ethoxy] -ethyl.} j] sulphamoyl) -carbamate, and acid addition salts thereof
MX2012015198A 2010-06-24 2011-06-24 PREPARATION OF 13-CYCLOHEXYL-3-METHOXY-6-[METHYL-(2-{2-[METHYL-(S ULPHAMOYL)-AMINO]-ETHOXY}-ETHYL)-CARBAMOYL]-7<i>H</i>-INDOLO-[2, 1-a]-[2]-BENZAZEPINE-10-CARBOXYLIC ACID. MX2012015198A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP10167221 2010-06-24
PCT/EP2011/060606 WO2011161232A1 (en) 2010-06-24 2011-06-24 PREPARATION OF 13-CYCLOHEXYL-3-METHOXY-6-[METHYL-(2-{2-[METHYL-(SULPHAMOYL)-AMINO]-ETHOXY}-ETHYL)-CARBAMOYL]-7H-INDOLO-[2,1-a]-[2]-BENZAZEPINE-10-CARBOXYLIC ACID

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JP (1) JP5870098B2 (en)
CN (1) CN103097356B (en)
AU (1) AU2011268922B2 (en)
BR (1) BR112012032889A2 (en)
CA (1) CA2801517C (en)
IL (1) IL223427A (en)
MX (1) MX2012015198A (en)
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WO (1) WO2011161232A1 (en)

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TWI454476B (en) 2008-07-08 2014-10-01 Tibotec Pharm Ltd Macrocyclic indole derivatives useful as hepatitis c virus inhibitors

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US6054472A (en) 1996-04-23 2000-04-25 Vertex Pharmaceuticals, Incorporated Inhibitors of IMPDH enzyme
US5807876A (en) 1996-04-23 1998-09-15 Vertex Pharmaceuticals Incorporated Inhibitors of IMPDH enzyme
AU723730B2 (en) 1996-04-23 2000-09-07 Vertex Pharmaceuticals Incorporated Urea derivatives as inhibitors of IMPDH enzyme
JP4327910B2 (en) 1997-03-14 2009-09-09 バーテックス ファーマシューティカルズ インコーポレイテッド Inhibitors of IMPDH enzyme
CZ301802B6 (en) 1999-03-19 2010-06-30 Vertex Pharmaceuticals Incorporated Urea derivatives as IMPDH inhibitors and pharmaceutical compositions comprising these derivatives
KR100891240B1 (en) 2000-08-30 2009-04-01 파나소닉 주식회사 Plasma display unit and production method thereof
US7153848B2 (en) 2004-08-09 2006-12-26 Bristol-Myers Squibb Company Inhibitors of HCV replication
WO2007026024A2 (en) 2005-09-02 2007-03-08 Tibotec Pharmaceuticals Ltd. Benzodiazepines as hcv inhibitors
US7399758B2 (en) 2005-09-12 2008-07-15 Meanwell Nicholas A Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors
GB0522881D0 (en) 2005-11-10 2005-12-21 Angeletti P Ist Richerche Bio Therapeutic compounds
WO2007092000A1 (en) 2006-02-06 2007-08-16 Bristol-Myers Squibb Company Inhibitors of hcv replication
US7521443B2 (en) 2006-05-17 2009-04-21 Bristol-Myers Squibb Company Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors
US7456166B2 (en) 2006-05-17 2008-11-25 Bristol-Myers Squibb Company Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors
US7521441B2 (en) 2006-05-22 2009-04-21 Bristol-Myers Squibb Company Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors
US7521442B2 (en) * 2006-05-25 2009-04-21 Bristol-Myers Squibb Company Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors
CA2672250C (en) 2006-12-20 2013-04-30 Ian Stansfield Antiviral indoles
CN101754970B (en) 2007-07-17 2013-07-10 P.安杰莱蒂分子生物学研究所 Macrocyclic indole derivatives for the treatment of hepatitis c infections
TWI454476B (en) * 2008-07-08 2014-10-01 Tibotec Pharm Ltd Macrocyclic indole derivatives useful as hepatitis c virus inhibitors

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BR112012032889A2 (en) 2015-09-15
RU2013103004A (en) 2014-07-27
US9127010B2 (en) 2015-09-08
RU2559886C2 (en) 2015-08-20
CA2801517A1 (en) 2011-12-29
CN103097356A (en) 2013-05-08
EP2585438B1 (en) 2014-08-20
IL223427A (en) 2015-04-30
JP2013530976A (en) 2013-08-01
US20150329482A1 (en) 2015-11-19
AU2011268922A1 (en) 2013-01-10
JP5870098B2 (en) 2016-02-24
AU2011268922B2 (en) 2014-06-12
WO2011161232A1 (en) 2011-12-29
EP2585438A1 (en) 2013-05-01
CA2801517C (en) 2017-12-12
CN103097356B (en) 2016-01-13
US20130102777A1 (en) 2013-04-25

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